Meetings & Conferences Software and Tools

Building a New Biology (BioSysBio 2009)

Drew Endy
Stanford University, and BioBricks Foundation

Overview: Puzzle related to SB and informing some of his engineering work. Then a ramble through the science of genetics. Last part is a debrief on BioBrick public agreements.

Part 1. If SB is going to scale, we really need to think about the underlying "physics engine", you could do worse than look to Gillespie's work on a well-mixed system. This underlies much of the stochastic systems that underly SB, such as the differentiation of stem cells. A lot of work is based on this idea. Another good system is phage lambda: a phage infects a cell, leading to two outcomes: lysogen + dormancy, or lysing of the cell. If you infect 100 cells with exactly 1 phage molecule each, you get a distribution of behaviour. How is the physics working here? How does an individual cell decide which fate is in store? About 10 years ago, A Arkin took this molecular biology and mapped it to a physics model. From this model it became clear how this variability arises. Can you predetermine what cell fate will occur before lamba infects it? Endy looked into this. They collected different types of cells: both tiny and large (e.g. with the latter, about to divide and with the former just after division). They then scored each cell for the different fates. In the tiny cells, lysogeny is favored 4 to 1, whereas in big cells, lysis is favored 4 to 1. In the end, this is a deterministic model. There might be some discrete transition where certain parts of the cell cycle favor certain fates. They found, however, that there was a continuous distribution of lysis/lysogeny. Further examination found that there was a third, mixed fate. This is that the cell divides before it decides what to do, and the daughter cells will then decide what to do.

They have looked at this process in time, and how it works at the single-cell level. N is a protein made almost immediately upon infection – its activity is not strongly coordinated with cell fate. Cll *is* strongly associated, however. Q protein also studied. In a small bacterium, 100 molecules of repressor are constrained more in the physical sense, so you need 400 of Cro to balance; while in a bigger bacterium there is more space and only 100 Cro are needed. However, this theory may not work as the things may take too long to be built.

Part 2. How much DNA is there on earth? Well, it must be finite. he's not sure about these numbers1E10 tons bacteria (5% DNA)… 5E35 bp on the planet. How long would it take us to sequence it? A conservative estimate – and a little out of date – is about 5E23 months – one mole of months! If current trends hold, a typical RO1 (grant) in 2090 could have: sequence all DNA on earth in the first month of project. 🙂

If there is a finite amount of dna on the planet, could we finish the science of genetics or SB? If true, could we then finish early? Is genetics bounded? Well, if these three things hold true, perhaps yes: genomes have finite lengths; Fixation of rates of mutants in poopulations are finite; Atrophy rates of functional genetic elements are > 0.

Is the underlying math equal to perturbation design? Take the bacteriophage T7 (references a 1969 paper about it from Virology): in that, 19 genes have been identified by isolating the mutants and expect 10 more. By 1989 the sequence came out, and there were acutally 50 genes. So, mutagenesis and screening only got some of the genes. About 40% of the elements didn't have a function assigned.

Could a biologist fix a radio? Endy's question is: could an engineer fix an evolved radio (see Koza et al.)?

Part 3. Who owns BioFAB? What legal things do we need to do for BioBricks? Patents are slow and expensive, copyright is cheap but does not apply, and various other things have other problems. Therefore they have drafted the BioBrick Public Agreements document. He then showed the actual early draft document. They're trying to create a commons of free parts. Open Technology Platform for BioBricks.

Personal Comments: Best statement from Endy: "Really intelligent design would have documentation." (Not sure if it is his statement, or attributed to someone else).

Wednesday Session 3

Please note that this post is merely my notes on the presentation. They are not guaranteed to be correct, and unless explicitly stated are not my opinions. They do not reflect the opinions of my employers. Any errors you can happily assume to be mine and no-one else's. I'm happy to correct any errors you may spot – just let me know!

Read and post comments |
Send to a friend


Meetings & Conferences Standards

Standards for Synthetic Biology (BioSysBio 2009)

Existing Standards for DNA Description

Guy Cochrane

For the EMBL database, they need to provide capability for submission and collaborator data exchange. They use SRS for text search and retrieval, simple sequence retrieval (dbfetch), also dump the whole set of files out. There's been a large amount of growth over the past year or so, as the new technologies allow much faster sequencing.

Personal Comment: I took fewer notes for this section as I used to work on TrEMBL (UniProt as it's called now) and am quite familiar with EMBL, so I didn't feel the need to take as many notes…!

Previous Standards Effort: SBML

Herbert Sauro
University of Washington, Seattle

In 1999 there were 5-6 different simulators, and people wanted to be able to move the models from one tool to the next. SBML was originally created to represent homogeneous multi-compartment biochemical systems. They estimate that this format can cover about 80% of the models out there. The initial version was funded by JST. Over 120 software packages now support SBML including MATLAB and Mathematica. SBML is also acceptable to many journals including Nature, Science, and PLoS. It has also since spawned many other initiatives.

Key contributing factors to its take up: a need from the community; availability of detailed documentation; annual/biannual two-day meetings; portable software libraries to enable developers to incorporate standard capabilities into their software; they deliberately didn't try to do everything, as it covered about 80% of the community's needs at the time. Because the libraries were maintained centrally it ensured that the standard didn't diverge, and extensions/modifications were agreed by the community and could then be easily incorporated by developers.

SBML has been going for 8 years. Significant changes are planned. But, the exciting things are the peripheral results: BioModels (repository), KiSAO (ontology/CV), SBO (ontology/CV), TEDDY (ontology/CV), MIASE (presumptive standard for storage of simulation results), SBRML (presumptive standard), Antimony (human-readable version of SBML).

With a standard format, you can all of a sudden do compliance testing – do all applications produce the same results, or even succeed when simulating all models in BioModels? roadRunner, COPASI, BioUML, SBML ODE Solver perform the best.

Physical Standards and the BioBrick Registry

Randy Rettberg

The idea of the registry came from the TTL Data Book for design engineers. The current registry contains a wiki and more – it looks like a website, not a data book. Each biobrick part was listed, and had its own page. The number of teams in 2003 was less than 10 – in 2008 it was 84, with 1180 people.

The quality of the parts is really important. Starting last year, they did a specific set quality control tests. They're making sure that the top 800 bricks grew, had good sequence, the users said they worked, etc.

They also worked on the overall structure of the registry. He'd like to go in the direction of a more distributed system. Future work includes: extension to DAS interface; uploading parts; external tool hooks for sequence analysis and sequence and feature editors.

This session is a preface session for tomorrow's end-of-meeting standards workshop. Beer and pizza!

Tuesday Standards Session

Please note that this post is merely my notes on the presentation. They are not guaranteed to be correct, and unless explicitly stated are not my opinions. They do not reflect the opinions of my employers. Any errors you can happily assume to be mine and no-one else's. I'm happy to correct any errors you may spot – just let me know!

Read and post comments |
Send to a friend